ABSTRACT: Usually transplant operations are performed as a lifesaving measure, e.g., for end-stage hepatic or renal failure, and the subsequent morbidities encountered as a result of immunosuppressive drug regimens must be accepted since there is no other choice. In contrast, the elective surgery performed to transplant new limbs, hands and even faces from cadaveric donors to severely injured recipients is done to improve their quality of life. This fundamental difference generates controversy and ethical dilemmas since often the intense immunosuppressive regime needed to maintain this type of ?vascularized composite allotransplantation? (VCA) leads to serious morbidities and risk of death from diseases such as diabetes, nephrotoxicity, hepatotoxicity, and cancer in patients who would otherwise be alive, although living with terrible disabilities. Moreover, despite the tremendous progress that has been made in the complex surgery needed for VCA, the rejection rate remains disappointingly high. Therefore, new strategies that can prolong the survival of composite tissue grafts while reducing post-transplant toxicities are needed for these patients. Our group has published that adrenergic signaling suppresses the immune response following allogenic stem cell transplantation (thus reducing graft vs host disease). In this proposal, a surgeon and an immunologist, each experienced in translational research, are collaborating to test, for the first time, the hypothesis that adrenergic signaling can be manipulated to suppress the immune response leading to graft rejection in VCA recipients. We are proposing to repurpose well studied and clinically safe ?-adrenergic receptor (?-AR) agonists to inhibit the anti-graft immune response and thus prolong graft survival. If successful, this could also allow reduced dosing levels of currently used, toxic immunosuppressive drugs. To obtain proof-of-principle information supporting this novel (and immediately clinically applicable) hypothesis, we propose two aims: Aim 1 will use a murine model of VCA developed by our team, to test the effect of a ?2- specific agonist on graft survival in combination with various doses of a standard immunosuppressive drug. We will also characterize changes in the immune cell repertoire and function that occur with ?2-agonist treatment since we believe that suppression of anti-graft immunity is the major mechanism by which ?2-AR signaling can improve graft survival. Aim 2 will validate the specific contribution of ?2-adrenergic signaling in immune cells by using ?2-AR knockout mice for either the donor composite graft or the host- allowing us to distinguish between ?2-AR signaling in the immune cells compartment vs. the stromal cells, following VCA. The proposed studies are predicted to identify, for the first time, the beneficial impact of ?-AR signaling on VCA survival and help generate necessary preclinical evidence needed to bring this strategy to the clinic. If successful, our approach could be extended to benefit other organ transplantations such as liver or kidney in which post-surgical morbidity is also a major problem with conventional immunosuppressive regimens.